Check patentability & draft patents in minutes with Patsnap Eureka AI!

A kind of synthetic method of apixaban and its intermediate

A kind of synthetic method, the technology of apixaban, be used in the relevant intermediate and preparation field thereof

Active Publication Date: 2016-11-30
ZHEJIANG TIANYU PHARMA
View PDF6 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There is also no report on the synthesis of apixaban from compound 8

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • A kind of synthetic method of apixaban and its intermediate
  • A kind of synthetic method of apixaban and its intermediate
  • A kind of synthetic method of apixaban and its intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0099] Example 1: 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7- The synthesis of tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonitrile (i.e. compound 8) was carried out according to the following scheme:

[0100]

[0101] 1) Preparation of Compound 11

[0102] In reaction bottle, add 52g (0.25mol) compound 9, 75g (0.30mol) compound 10, 25g (0.30mol) sodium acetate (or inorganic base or inorganic base as mentioned above), 600mL toluene, add, be warming up to Stir at 90-95°C for 4 hours, monitor the liquid phase until the reaction is complete, then slowly cool the reaction solution to 0°C, a large amount of light yellow solid precipitates, filter the obtained solid, wash once with 200mL of water at 50-60°C, and then use acetic acid Ethyl ester was recrystallized to obtain 84 g of light yellow solid with a yield of 86%.

[0103] 1 H-NMR (400MHz, CDCl 3)δ: 8.16(dd, J=4.8Hz, J=1.6Hz, 2H), 7.43(dd, J=4.8Hz, J=1.6Hz, 2H), 7.37(dd, J=4.8Hz, J=1.6Hz , 2H),...

Embodiment 2

[0122] Embodiment 2: Preparation of Apixaban

[0123]

[0124] Add 4.4g (0.01mol) of compound 8, 1.5g (0.011mol) of potassium carbonate (or other carbonates as mentioned above), 20mL of ethanol to the reaction flask, and cool the reaction solution to 0-5°C after the addition , slowly add 8g of 30% hydrogen peroxide dropwise, after the drop is completed, slowly rise to room temperature and keep warm for 5 hours, monitor the liquid phase until the reaction is complete, concentrate under reduced pressure, wash the obtained solid twice with 50mL water, filter, and recrystallize the obtained solid with ethanol, After vacuum drying, 4.0 g of white crystals were obtained, with a yield of 89%.

[0125] 1 H-NMR (400MHz, CDCl 3 )δ: 7.49(d, J=8.8Hz, 2H), 7.37(d, J=9.1Hz, 2H), 7.26(d, J=8.8Hz, 2H), 6.98(s, 1H), 6.95(d, J=9.2Hz, 2H), 6.28(s, 1H), 4.14(t, J=6.6Hz, 2H), 3.81(s, 3H), 3.61(m, 2H), 3.39(t, J=6.6Hz, 2H), 2.63(t, J=6.2Hz, 2H), 1.96(m, 4H).

[0126] 13 C-NMR (100MHz, CDCl...

Embodiment 3

[0127] Embodiment 3: Preparation of Apixaban

[0128]

[0129] Add 4.4g (0.01mol) compound 8, 0.44g (0.011mol) sodium hydroxide (or other hydroxides as mentioned above), 30mL ethanol (or other lower alcohols as mentioned above) in the reaction flask, After the addition, the temperature of the reaction solution was lowered to 0-5°C, and 8 g of 30% hydrogen peroxide was slowly added dropwise. After the drop was completed, it was slowly raised to room temperature and then kept for 4 hours. The liquid phase was monitored until the reaction was complete, concentrated under reduced pressure, and the obtained solid was washed with 60 mL of water. Twice, filtered, the obtained solid was recrystallized with ethanol, and after vacuum drying, 4.3 g of white crystals were obtained, with a yield of 94%. The molecular structure of the resulting product was 1 H-NMR, 13 C-NMR, MS characterization is consistent with the spectrogram of the product obtained in Example 2.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention provides a synthetic method of apixaban described in the specification, wherein the apixaban is obtained by performing hydrolysis reaction on a compound 8 and hydrogen peroxide in the presence of alkaline. The invention further discloses a preparation method of the compound, wherein the preparation method is described in the following scheme. The invention further provides an intermediate as shown in structural formulas 11, 12 and 13 of the apixaban. The synthetic method disclosed by the invention can be used for effectively avoiding side reactions such as ester exchange and hydrolysis in a process of synthesizing the apixaban, is beneficial to control over the apixaban quality; the reaction conditions are relatively simple and convenient, mild and environmentally friendly, the requirements on equipment are not high, the dosage of the auxiliary reagent is relatively small, the use of an ammonia source is avoided, the reaction yield of each step is relatively high, the auxiliary materials are less, the total cost is low, and thus, the synthetic method is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a synthesis method of a new antithrombotic drug apixaban, related intermediates and a preparation method thereof. Background technique [0002] Apixaban, the English name is Apixaban (trade name: Eliquis), the Chinese chemical name is 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1- Piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, CAS No. 503612-47-3, has the following chemical Structural formula: [0003] [0004] Apixaban is an antithrombotic drug. It is a direct factor Xa inhibitor jointly developed by Bristol-Myers Squibb and Pfizer. It was approved for marketing in the European Union in March 2011 and approved by the FDA in December 2012. The drug was launched in the United States. [0005] Multiple publications include patents WO03026652, WO03049681, CN101967145B, CN102675314A, US7396932 and documents Ramirez A., et.al, J.Org.Chem.2012,77,775...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 王臻占付灵肖金华张毅屠勇军
Owner ZHEJIANG TIANYU PHARMA
Features
  • R&D
  • Intellectual Property
  • Life Sciences
  • Materials
  • Tech Scout
Why Patsnap Eureka
  • Unparalleled Data Quality
  • Higher Quality Content
  • 60% Fewer Hallucinations
Social media
Patsnap Eureka Blog
Learn More

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2025 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com